Investigating isoform‐specific functions of Tau under healthy and pathological conditions using Tau‐deficient hiPSC‐derived cortical neurons

Background One hallmark of many neurodegenerative diseases, such as Alzheimer’s disease (AD), is the formation of neurofibrillary tangles by hyperphosphorylated Tau in the brain, resulting in neuronal death and cognitive decline. In the adult human brain, six Tau isoforms are expressed, originating...

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Bibliographic Details
Published in:Alzheimer's & dementia 2021-12, Vol.17 (S2), p.e058005-n/a
Main Authors: Bachmann, Sarah, Bell, Michael, Kabbani, Mhd. Aghyad Al, Klimek, Jennifer, Zempel, Hans
Format: Article
Language:English
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Summary:Background One hallmark of many neurodegenerative diseases, such as Alzheimer’s disease (AD), is the formation of neurofibrillary tangles by hyperphosphorylated Tau in the brain, resulting in neuronal death and cognitive decline. In the adult human brain, six Tau isoforms are expressed, originating from alternative splicing of exons 2, 3, and 10 of the MAPT gene. The isoforms differ in the number of N‐terminal inserts (0, 1, or 2N) and the C‐terminal repeat number (3 or 4R). Mutations affecting splicing of the MAPT gene can alter the Tau isoform ratio and ultimately cause neurodegeneration. Recent results from murine neurons highlight that the six human‐specific isoforms are differentially localized within neurons and influence microtubule dynamics in an isoform‐specific manner. Method To further investigate the Tau isoforms in a human neuronal model, we generated three Tau KO iPSC cell lines derived from Ngn2‐WTC11 cells using CRISPR/Cas9. Result Basic characterization of the Tau KO cell lines showed no difference in the morphology or pluripotency of iPSCs, the capability of neuronal differentiation or neuronal morphology compared to WT iPSCs and induced neurons. Initial results from re‐expressed TAU isoforms in Tau KO human neurons support the differential localization of the isoforms observed previously. Further experiments will investigate the isoform‐specific role of Tau regarding microtubule dynamics, axonal branching, and synapse formation under basal and pathological conditions. Conclusion Expected results will provide a major understanding of basic biological functions of Tau and help to identify potential therapeutic targets for the treatment of AD and related neurodegenerative diseases.
ISSN:1552-5260
1552-5279
DOI:10.1002/alz.058005